Targeted Overexpression of Noncleavable and Secreted Forms of Tumor Necrosis Factor Provokes Disparate Cardiac Phenotypes

Abstract

Background-Recent studies suggest that posttranslation processing or "shedding" (ie, secretion) of tumor necrosis factor (TNF) by tumor necrosis factor-␣ converting enzyme (TACE) may contribute to the left ventricular (LV) remodeling that occurs in the failing human heart. Methods and Results-To address the functional significance of TNF shedding, we generated lines of transgenic mice with targeted overexpression of secreted wild-type (MHCsTNF 2 ) TNF and overexpression of a mutated noncleavable transmembrane form of TNF (MHCmTNF). Both lines of mice had overlapping levels of myocardial TNF protein; however, the phenotypes of the MHCsTNF2 and MHCmTNF mice were strikingly disparate. Whereas the MHCmTNF mice developed a concentric LV hypertrophy phenotype, the MHCsTNF 2 mice developed a dilated LV phenotype. The fibrillar collagen weave in MHCmTNF mice with concentric hypertrophy was characterized by thick collagen fibrils and increased collagen content, whereas the fibrillar collagen weave in the MHCsTNF 2 mice with LV dilation was characterized by a diminished collagen content. Inhibition of matrix metalloproteinases with a broad-based matrix metalloproteinase inhibitor prevented LV dilation in the MHCsTNF 2 mice. Conclusions-These findings suggest that posttranslational processing of TNF, as opposed to TNF expression per se, is responsible for the adverse cardiac remodeling that occurs after sustained TNF overexpression.

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…In any way, an overall outcome of glutathione repletion is the disruption of the TNF-α/ TNF-R1/ N-SMase signalling cycle. In fact, the effects of NAC treatment resemble those provided by TNF-α or TNF-R1 ablation, opposite to the deleterious effects brought by sTNF-α overexpression [48]. Thus, ablation of TNF-R1 or TNF-α in mice leads to a better post-MI preservation of the cardiac function compared with post-MI WT mice [49,50].…”

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

“…Further research demonstrated that the myocardial ECM maintains alignment of myofibrils within the myocyte through a collagen-integrincytoskeleton-myofibril relation (50,132,254,365,367,395,398,441). In addition to a fibrillar collagen network, a basement membrane, proteoglycans, and glycosaminoglycans, the myocardial ECM contains a large reservoir of bioactive molecules (17,34,41,64,89,95,101,109,111,114,188,288,360,362,492). For example, it has been demonstrated that the concentration of bioactive signaling molecules such as angiotensin II (ANG II) and endothelin (ET)-1 are over 100-fold higher within the myocardial interstitium than in plasma (89,101,288,492).…”

“…For example, it has been demonstrated that the concentration of bioactive signaling molecules such as angiotensin II (ANG II) and endothelin (ET)-1 are over 100-fold higher within the myocardial interstitium than in plasma (89,101,288,492). Moreover, cytokine activation and signaling such as that for tumor necrosis factor-␣ (TNF) is highly compartmentalized within the myocardial interstitium (95,111). Growth factors such as transforming growth factor-␤ (TGF) are stored in a latent form within the myocardial interstitium and thereby form a reservoir of signaling molecules that directly influence myocardial ECM synthesis and degradation (67,82,218,298,399,443).…”

Cutting Edge: Tissue Inhibitor of Metalloproteinase 3 Regulates TNF-Dependent Systemic Inflammation

“…Membranebound and cleaved TNF have distinct physiological effects as demonstrated in models of heart disease, arthritis, and systemic shock (3)(4)(5). Biochemically, p75/TNFRSF1B is more easily activated by membrane-bound TNF, whereas p55/TNFRSF1A readily responds to soluble TNF (5).…”